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Thromb Haemost
DOI: 10.1055/a-2565-2449
Coagulation and Fibrinolysis

Hyperfibrinolysis is Associated with Complement Activation Following Trauma

Christopher D. Barrett   *
1   Division of Acute Care Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, United States
2   Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, United States
,
Elizabeth R. Maginot    *
1   Division of Acute Care Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, United States
,
Ernest E. Moore
3   Department of Surgery, Ernest E Moore Shock Trauma Center at Denver Health, Denver, Colorado, United States
4   Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
,
Collin M. White
1   Division of Acute Care Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, United States
,
Hunter B. Moore
5   Department of Surgery, Advent Health Porter, Denver, Colorado, United States
,
Isabella M. Bernhardt
6   Hunter College, New York, New York, United States
,
Trace B. Moody
1   Division of Acute Care Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, United States
,
James G. Chandler
3   Department of Surgery, Ernest E Moore Shock Trauma Center at Denver Health, Denver, Colorado, United States
,
Flobater I. Gawargi
2   Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, United States
,
Reynold Henry
1   Division of Acute Care Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, United States
,
Dominik F. Draxler
7   Department of Cardiology and Bern Center for Precision Medicine, University Hospital of Bern, Bern, Switzerland
,
Martin A. Schreiber
8   Department of Surgery, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States
,
Robert L. Medcalf
9   Molecular Neurotrauma and Haemostasis Laboratory, Australian Centre of Blood Diseases, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia
,
Angela Sauaia
10   Sauaia Statistical Solutions, L.L.C., Denver, Colorado, United States
› Author Affiliations Funding This study was supported in part by National Heart, Lung, and Blood Institute grant K08-HL171936 (CDB), and National Institute of General Medical Sciences grants P20-GM152326 (CDB) and T32-GM008315 (EEM, AS).
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Abstract

Background

Complement is activated after trauma, but the activation mechanism is unknown. Plasmin can directly activate C3 and C5, and four distinct fibrinolytic phenotypes have now been recognized after injury—hyperfibrinolysis, fibrinolysis shutdown, hypofibrinolysis, and nonpathologic/physiologic.

Objectives

We set out to investigate whether a relationship between complement activation and fibrinolysis was present in adult trauma patients (n = 56).

Methods

Rapid and tPA-challenged thromboelastography (TEG) was performed in the emergency department with IRB approval, and plasma obtained for C3a, C4a, C5a, Ba, sC5b-9, Factor I, Factor H, active PAI-1, α-2 antiplasmin (A2AP), plasmin-antiplasmin complex (PAP), and tPA activity measurement via multiplex, ELISA and activity assays. Data were analyzed using ANOVA and Spearman's correlations. Significance was set at p < 0.05.

Results

C3a and sC5b-9 were significantly higher in patients with hyperfibrinolysis than with physiologic or hypofibrinolysis (p < 0.05). Elevations in C3a, C4a, and SC5b9, along with depletion of Factors H and I, were significantly associated with massive transfusion within 6 hours and postinjury death. There were significant positive correlations between multiple markers of fibrinolysis and complement activation markers and significant negative correlations with Factors H and I. Significant negative correlations between fibrinolytic inhibitors and complement activation were also observed.

Conclusion

Our findings suggest that fibrinolysis may play a direct role in complement activation in trauma through plasmin-mediated cleavage of C3 and C5.

Keywords

complement - fibrinolysis - trauma - inflammation - tranexamic acid (TXA)

Authors' Contribution

C.D.B. and E.R.M. prepared the manuscript with critical input, data interpretation, and revisions from all other listed authors.


* These authors are co-first author.




Publication History

Received: 15 November 2024

Accepted: 24 March 2025

Accepted Manuscript online:
25 March 2025

Article published online:
30 April 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

  • References

  • 1 Centers for Disease Control NCfIPaC. Web-based Injury Statistics Query and Reporting System (WISQARS). Accessed October 12, 2024; available at: https://www.cdc.gov/injury/wisqars/leadingcauses.html
    PubMed
  • 2 Cardenas JC, Wade CE, Cotton BA. et al; PROPPR Study Group. TEG lysis shutdown represents coagulopathy in bleeding trauma patients: analysis of the PROPPR cohort. Shock 2019; 51 (03) 273-283
    CrossrefPubMedSearch in Google Scholar
  • 3 Cotton BA, Harvin JA, Kostousouv V. et al. Hyperfibrinolysis at admission is an uncommon but highly lethal event associated with shock and prehospital fluid administration. J Trauma Acute Care Surg 2012; 73 (02) 365-370 , discussion 370
    CrossrefPubMedSearch in Google Scholar
  • 4 Kimura A, Ikeo K, Nonaka M. Evolutionary origin of the vertebrate blood complement and coagulation systems inferred from liver EST analysis of lamprey. Dev Comp Immunol 2009; 33 (01) 77-87
    PubMedSearch in Google Scholar
  • 5 Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol 2010; 11 (09) 785-797
    CrossrefPubMedSearch in Google Scholar
  • 6 Amara U, Flierl MA, Rittirsch D. et al. Molecular intercommunication between the complement and coagulation systems. J Immunol 2010; 185 (09) 5628-5636
    CrossrefPubMedSearch in Google Scholar
  • 7 Barrett CD, Moore HB, Kong YW. et al. Tranexamic acid mediates proinflammatory and anti-inflammatory signaling via complement C5a regulation in a plasminogen activator-dependent manner. J Trauma Acute Care Surg 2019; 86 (01) 101-107
    CrossrefPubMedSearch in Google Scholar
  • 8 Barrett CD, Hsu AT, Ellson CD. et al. Blood clotting and traumatic injury with shock mediates complement-dependent neutrophil priming for extracellular ROS, ROS-dependent organ injury and coagulopathy. Clin Exp Immunol 2018; 194 (01) 103-117
    CrossrefPubMedSearch in Google Scholar
  • 9 Fosse E, Pillgram-Larsen J, Svennevig JL. et al. Complement activation in injured patients occurs immediately and is dependent on the severity of the trauma. Injury 1998; 29 (07) 509-514
    PubMedSearch in Google Scholar
  • 10 Ganter MT, Brohi K, Cohen MJ. et al. Role of the alternative pathway in the early complement activation following major trauma. Shock 2007; 28 (01) 29-34
    PubMedSearch in Google Scholar
  • 11 Burk AM, Martin M, Flierl MA. et al. Early complementopathy after multiple injuries in humans. Shock 2012; 37 (04) 348-354
    PubMedSearch in Google Scholar
  • 12 Mannes M, Schmidt CQ, Nilsson B, Ekdahl KN, Huber-Lang M. Complement as driver of systemic inflammation and organ failure in trauma, burn, and sepsis. Semin Immunopathol 2021; 43 (06) 773-788
    PubMedSearch in Google Scholar
  • 13 Moore HB, Moore EE, Gonzalez E. et al. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spectrum of postinjury fibrinolysis and relevance to antifibrinolytic therapy. J Trauma Acute Care Surg 2014; 77 (06) 811-817 , discussion 817
    CrossrefPubMedSearch in Google Scholar
  • 14 Moore HB, Barrett CD, Moore EE, Pieracci FM, Sauaia A. Differentiating pathologic from physiologic fibrinolysis: not as simple as conventional thrombelastography. J Am Coll Surg 2024; 239 (01) 30-41
    CrossrefPubMedSearch in Google Scholar
  • 15 Moore HB, Moore EE, Liras IN. et al. Acute fibrinolysis shutdown after injury occurs frequently and increases mortality: a multicenter evaluation of 2,540 severely injured patients. J Am Coll Surg 2016; 222 (04) 347-355
    CrossrefPubMedSearch in Google Scholar
  • 16 Meizoso JP, Karcutskie CA, Ray JJ, Namias N, Schulman CI, Proctor KG. Persistent fibrinolysis shutdown is associated with increased mortality in severely injured trauma patients. J Am Coll Surg 2017; 224 (04) 575-582
    CrossrefPubMedSearch in Google Scholar
  • 17 Cardenas JC, Matijevic N, Baer LA, Holcomb JB, Cotton BA, Wade CE. Elevated tissue plasminogen activator and reduced plasminogen activator inhibitor promote hyperfibrinolysis in trauma patients. Shock 2014; 41 (06) 514-521
    CrossrefPubMedSearch in Google Scholar
  • 18 Berkenpas MB, Lawrence DA, Ginsburg D. Molecular evolution of plasminogen activator inhibitor-1 functional stability. EMBO J 1995; 14 (13) 2969-2977
    CrossrefPubMedSearch in Google Scholar
  • 19 Thwaites RS, Gunawardana NC, Broich V. et al. Biphasic activation of complement and fibrinolysis during the human nasal allergic response. J Allergy Clin Immunol 2018; 141 (05) 1892-1895.e6
    PubMedSearch in Google Scholar
  • 20 Peerschke EI, Valentino A, So RJ, Shulman S. Ravinder, Thromboinflammation supports complement activation in cancer patients with COVID-19. Front Immunol 2021; 12: 716361
    PubMedSearch in Google Scholar
  • 21 Foley JH, Walton BL, Aleman MM. et al. Complement activation in arterial and venous thrombosis is mediated by plasmin. EBioMedicine 2016; 5: 175-182
    CrossrefPubMedSearch in Google Scholar
  • 22 Zhang M, Takahashi K, Alicot EM. et al. Activation of the lectin pathway by natural IgM in a model of ischemia/reperfusion injury. J Immunol 2006; 177 (07) 4727-4734
    PubMedSearch in Google Scholar
  • 23 Barrett CD, Kong YW, Yaffe MB. Influence of tranexamic acid on inflammatory signaling in trauma. Semin Thromb Hemost 2020; 46 (02) 183-188
    PubMedSearch in Google Scholar
  • 24 Rowell SE, Meier EN, McKnight B. et al. Effect of out-of-hospital tranexamic acid vs placebo on 6-month functional neurologic outcomes in patients with moderate or severe traumatic brain injury. JAMA 2020; 324 (10) 961-974
    PubMedSearch in Google Scholar
  • 25 Garrett MC, Otten ML, Starke RM. et al. Synergistic neuroprotective effects of C3a and C5a receptor blockade following intracerebral hemorrhage. Brain Res 2009; 1298: 171-177
    PubMedSearch in Google Scholar
  • 26 Flierl MA, Perl M, Rittirsch D. et al. The role of C5a in the innate immune response after experimental blunt chest trauma. Shock 2008; 29 (01) 25-31
    PubMedSearch in Google Scholar
  • 27 Barrett CD, Vigneshwar N, Moore HB. et al. Tranexamic acid is associated with reduced complement activation in trauma patients with hemorrhagic shock and hyperfibrinolysis on thromboelastography. Blood Coagul Fibrinolysis 2020; 31 (08) 578-582
    PubMedSearch in Google Scholar
  • 28 Albert-Weissenberger C, Mencl S, Hopp S, Kleinschnitz C, Sirén AL. Role of the kallikrein-kinin system in traumatic brain injury. Front Cell Neurosci 2014; 8: 345
    PubMedSearch in Google Scholar
  • 29 Hopp S, Albert-Weissenberger C, Mencl S. et al. Targeting coagulation factor XII as a novel therapeutic option in brain trauma. Ann Neurol 2016; 79 (06) 970-982
    CrossrefPubMedSearch in Google Scholar
  • 30 Huber-Lang M, Sarma JV, Zetoune FS. et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 2006; 12 (06) 682-687
    CrossrefPubMedSearch in Google Scholar
  • 31 Toy CR, Song H, Nagaraja HN. et al. The influence of an elastase-sensitive complement C5 variant on lupus nephritis and its flare. Kidney Int Rep 2021; 6 (08) 2105-2113
    PubMedSearch in Google Scholar
  • 32 Keshari RS, Silasi R, Lupu C, Taylor Jr FB, Lupu F. In vivo-generated thrombin and plasmin do not activate the complement system in baboons. Blood 2017; 130 (24) 2678-2681
    PubMedSearch in Google Scholar
  • 33 van Deventer SJ, Büller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990; 76 (12) 2520-2526
    CrossrefPubMedSearch in Google Scholar
  • 34 Campbell JC, Li Y, van Amersfoort E. et al. C1 inhibitor limits organ injury and prolongs survival in swine subjected to battlefield simulated injury. Shock 2016; 46 (3, suppl 1): 177-188
    PubMedSearch in Google Scholar